As a consequence of several separate lines of investigation pursued in this laboratory, evidence has been obtained which suggests that immunoregulation may involve factors in addition to antigen, sub-classes of antigen reactive lymphocytes, and their cellular products (antibodies, lymphokines). Specifically, the data suggest that the spleen may play an important role in control of the immune response. Based on these findings, we have advanced a simple hypothesis that attempts to account for certain aspects of immunoregulation which are under splenic control. The hypothesis seems readily amenable to experimental testing and requires the capacity to evaluate at a phenomenological level the role of the spleen in graft-rejection, auto- immunity, tolerance induction and graft-versus- host disease. It also requires that T and B lymphocytes be reproducibly and reliably identified by sophisticated in vitro methods and that this be done for the several laboratory species needed for these experiments. In addition, it is imperative that in vitro culture studies be carried out in an effort to reproduce the microenvironmental features which we feel are important to the role of the spleen. Our goal is to determine whether, by virtue of its unique cellular constitution and anatomic arrangement, the spleen modulates an immune response by converting a cell mediated reactivity into an antibody mediated one.